The previous cycles of this grant have supported our efforts to generate models of human congenital defects by screening ENU-mutagenized mice for recessive mutations affecting late embryonic development. These screens incorporated a genetic mapping component to facilitate the positional cloning and functional characterization of the mutant genes. The strategy has worked well, and we have generated many mice with phenotypes similar to human malformation syndromes and birth defects. Our future effort has even greater potential productivity, as the overall task of mutation discovery continues to be facilitated by rapid progress in technologies for genomic analysis. In this continuation proposal we aim to optimize several aspects of the project, while maintaining the fundamental approach that has thus far proven so productive. Specifically, we propose strategies for rapid mutant validation and for more rapidly translating gene discovery into functional analysis.